SUO 2017: Novel Targeted Androgen Ablation Prior to Radical Prostatectomy

Washington, DC (UroToday.com) Dr. Kibel from the Dana-Farber Cancer Institute discussed novel targeted androgen ablation prior to radical prostatectomy. Dr. Kibel commenced his presentation by noting that prostate cancer mortality for Gleason 8-10 disease treated with radical prostatectomy is high, providing clinical equipoise for assessing neoadjuvant options for perhaps improving outcomes in these at-risk patients.

Dr. Kibel highlighted that there are several randomized “historical” trials of radical prostatectomy +/- neoadjuvant hormone ablation, particularly in men with aggressive Gleason disease. Interestingly, these patients were only treated with 3 months of therapy and primarily in men with cT1c/cT2b disease, thus there were few meaningful results/endpoints garnered from these trials. Currently, there have been several “new” neoadjuvant trials for patients in this disease space. The general design of these studies includes patients with intermediate-high risk prostate cancer who are randomized to intense vs less intense ADT followed by radical prostatectomy. The primary endpoints are tissue androgen levels, and to assess partial complete response (pCR) and minimal residual disease (MRD) rate.

Neoadjuvant trials:

• TAPS trial: randomized men (n=35) to either LHRH agonist + bicalutamide, or LHRH agonist + dutasteride, or LHRH agonist + dutasteride + bicalutamide, or LHRH agonist + dutasteride + bicalutamide + ketoconazole. Prostate DHT levels were substantially lower in all experimental arms and two patients had complete pathologic response [1].

• Neoadjuvant abiraterone: High-risk prostate cancer patients (n=58) were randomized to either ADT + abiraterone (3 months) or ADT alone (3 months) followed by a prostate biopsy followed by ADT + abiraterone for all patients (3 months) followed by radical prostatectomy. Intraprostatic levels of DHT at the 12 week prostate biopsies were significantly lower in the ADT + abiraterone group, however prostatectomy pathologic staging demonstrated residual T3 or lymph node positive disease in the majority of patients [2].

• Neoadjuvant enzalutamide: High-risk prostate cancer patients (n=48) were randomized to LHRH agonist + dutasteride + enzalutamide or enzalutamide (6 months for each arm) followed by radical prostatectomy. In the enzalutamide arm, no patients achieved pCR or MRD, while in the experimental arm 4.3% achieve pCR and 13.0% MRD [3].

In a pooled analysis of the above three trials by Dr. Kibel and his group (in press), they found that the median time to BCR was 5.1 years (95%CI 4.4, NR) and 3-year BCR free rate was 70%. There were 5 patients that developed metastases correlating to a 3-year metastasis-free survival rate of 95% (95%CI 86%-98%); there was one prostate-cancer related death.

In summary, the neoadjuvant trials have demonstrated that longer and more intense ADT correlates with better pathologic response, and better pathologic response correlates with lower recurrence rate. Furthermore, we know that local therapy is effective, although many patients die of occult metastatic disease at the time of diagnosis, thus making the argument for neoadjuvant therapy. Although there are clear pathologic response and recurrence rate data, we await maturation of survival outcomes to see if there is an improvement in prostate cancer specific mortality.

References:

1. Mostaghel EA, Nelson PS, Lange P, et al. Targeted androgen pathway suppression in localized prostate cancer: A pilot study. J Clin Oncol 2014;32(3):229-237.
2. Taplin ME, Montgomery B, Logothetis CJ, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: Results of a randomized phase II neoadjuvant study. J Clin Oncol 2014;32(33):3705-3715.
3. Montgomery B, Tretiakova MS, Joshua AM, et al. Neoadjuvant enzalutamide prior to prostatectomy. Clin Cancer Res 2017;23(9):2169-2176.

Presented by: Adam S. Kibel, MD, Dana-Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, Society of Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC

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